Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. Epidemiological studies suggest that alcohol consumption also modulates the risk for the development of type 2 diabetes, the most common metabolic disease among older North Americans, with light alcohol consumption decreasing risk and chronic heavy alcohol consumption increasing risk in a J-shaped curve. Chronic, heavy ethanol exposure results in the development of glucose intolerance and hepatic insulin resistance. While the role of adipose tissue in the regulation of energy stores has long been appreciated, there is a growing understanding for the critical role of adipose tissue in regulating metabolic homeostasis, including the ability to modulate insulin sensitivity in skeletal muscle and liver, as well as contribute to the regulation of inflammatory responses. The long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic activity of adipose tissue and determine the impact of these chronic ethanol-induced changes in adipose tissue on the pathophysiological effects of chronic ethanol in liver. In the past granting period, we have shown that chronic ethanol feeding increases the infiltration of macrophages into adipose tissue associated with increased the expression of inflammatory cytokines and chemokines, as well as decreases in adiponectin secretion. Here we hypothesize that changes in the metabolic and regulatory activity of adipose tissue in response to chronic ethanol consumption are important contributors to the development of ethanol-induced liver injury. In this proposed renewal, we will investigate the mechanisms by which chronic ethanol exposure increases inflammatory cytokine expression and decreases adiponectin expression and secretion by adipose tissue. Utilizing mouse and rat models of chronic ethanol exposure, the specific aims of this proposal are to test the following hypotheses: 1) Ethanol-induced oxidant stress in adipose tissue leads to macrophage recruitment and an increased inflammatory milieu in adipose tissue. 2) Decreased circulating adiponectin after chronic ethanol exposure is due to ethanol-induced decreases in adiponectin expression and secretion and 3) Ethanol-induced disruption of adipose tissue metabolism, leading to decreased adiponectin secretion by adipose tissue, contributes to ethanol-induced liver injury. Understanding the mechanisms by which chronic ethanol disrupts the metabolic and regulatory activity of adipose tissue, and the impact of these changes on hepatic function, will likely lead to the development of novel therapeutic strategies to prevent and/or reverse alcoholic liver disease.